1. Field of the Invention
This invention relates to an improved regiospecific process for the synthesis of acyclic nucleosides such as, acyclovir and ganciclovir, anti-viral compounds especially effective against herpes virus, and intermediates thereof starting from diacylguanine and appropriate addendum, selected from 2-oxa-1,4-butanediol diacetate (OBDDA), 1,4-diacetoxy-3-acetoxymethyl-2-oxa-butane, 1,4-dibenzyloxy-3-acetoxymethyl-2-oxabutane.
2. Discussions of the Background
Both acyclovir (Ia) and ganciclovir (Ib) show remarkable anti-viral activities (U.S. Pat No. 4,199,574, U.S. Pat. No. 4,355,032) ##STR4## Ia: R=--CH.sub.2 --O--CH.sub.2 CH.sub.2 --OH (Acyclovir) Ib: R=CH.sub.2 --O--CH(CH.sub.2 OH)CH.sub.2 OH (Ganciclovir)
The strategy adopted in prior art for manufacture of I is alkylation of appropriately substituted 2-aminopurines eg. guanine derivatives with required addendum which essentially includes an acid with or without solvent to yield N-9 alkylated intermediate (II) eg. N.sup.2 -acetyl-9-[(2-acetoxyethoxy)methyl]guanine (IIa) along with corresponding N-7 alkylated isomer (IIIa). In particular, it is known to react mono or diacetylated guanine with 2-oxa-1,4-butanediol diacetate (OBDDA) to yield the intermediate compound of formula II. ##STR5## IIa: R.sup.1 =H, R.sup.2 =COCH.sub.3 IIb: R.sup.1 =CH.sub.2 OCH.sub.2 Ph, R.sup.2 =CH.sub.2 Ph
IIc: R.sup.1 =CH.sub.2 OCOCH.sub.3, R.sup.2 =COCH.sub.3 PA1 1. BE 833 006, U.S. Pat No. 4,199,574 describe a process for the synthesis of Acyclovir (Ia) which involves condensation of trimethylsilylated guanine with 2-benzoyloxyethoxy methyl chloride in DMF in the presence of a base followed by deprotection, yielding in the desired N-9 isomer (IIa) along with unacceptable amounts of its corresponding N-7 isomer (IIIa). The former after purification and deacetylation gives acyclovir in 24% overall yield. PA1 2. H. Matsumoto in Chem Pharm Bull, 36(3), 1153-1157 and JP 63-107982 teaches a process for the synthesis of acyclovir (Ia) by condensation of diacetyl guanine (DAG Va) with 2-oxa-1,4-butanediol diacetate (OBDDA, VIIa) in DMSO in presence of an acid catalyst to get a mixture of N-9/N-7 isomer (66:26). The former is isolated by column chromatography and deacetylated with methanolic ammonia to give acyclovir. Overall yield of acyclovir from guanine is 42% PA1 4. EP 532 878 describes a process in which a transgly cosilation reaction between guanosine, acetic anhydride and 2-oxa-1,4-butanediol diacetate (OBDDA) in the presence of catalytic amount of an acid is carried out, followed by hydrolysis to yield a mixture of acyclovir (Ia) and its N-7 isomer (IVa). The above process is illustrated in the following scheme B: ##STR10## PA1 1) condensation reaction between guanine and glyoxal, PA1 2) oxidation of the resulting tricyclic vicinal diol to N.sup.2 -formyl guanine. PA1 3) alkylation of N.sup.2 -formylguanine with OBDDA in the presence of an acid, PA1 4) hydrolysis of N.sup.2 -formyl-N.sup.9 alkylated guanine to Acyclovir. PA1 i) washing the crude intermediate (II) with a solvent selected from methanol, ethanol, iso-propanol, acetone, THF, dioxane, dimethoxyethane, acetonitrile, toluene, benzene, ethyl acetate, dichloromethane or mixture thereof to remove the traces of non-polar impurities. PA1 ii) deprotection of the various functional groups such as esters, or benzyl ethers of the intermediate (II) to yield pure N-9 isomer (I) i.e acyclovir or ganciclovir of extremely high purity.
alongwith compound of formula III ##STR6## Wherein the formula III includes the compound according to IIIa, IIIb and IIIc, with R.sup.1 and R.sup.2 as defined in formula IIa IIb and IIc respectively.
This intermediate mixture of II and III is purified generally by costly and tedious processes to remove the last traces of N-7 isomer (III) and then hydrolysed to yield I. Often N-7 isomer (IV) is associated with final product which is further removed employing a number of operations. ##STR7## Wherein for IVa and IVb, R is as defined in formula I.
Since alkylation of guanine derivatives like diacetyl/monoacetyl guanine (DAG/MAG) of formula V and VI ##STR8## in presence of an acid, is a thermodynamically controlled reaction, N-7 isomer of formula III is always formed. However, N-9 isomer (II) being thermodynamically more stable (Chem Pharm Bull, 1970, 18, 1446) is produced as the major product.
The formation of N-7 isomer (III) increases the total cost of manufacture. Hence, there is a need for development of regiospecific process for the manufacture of II, the penultimate intermediate for I.
Some of the important methods for manufacture of acyclovir/ganciclovir of formula I reported in the prior art are described below:
The process is illustrated in the following scheme A: ##STR9## 3. JP 59-80685 utilises similar chemistry but starts from N.sup.2 -monoacetyl guanine (MAG, VIb) in presence or absence of solvent to yield a mixture of N-9 and N-7 alkylated guanine derivatives (N-9/N-7 ratio 52:26). The former subsequently isolated and deprotected to give acyclovir in overall 43% yield.
It can be observed that the major drawback in all the processes described above is that acyclovir (Ia) or its intermediate (IIa) is always contaminated with substantial amount of its N-7 isomer, and hence the separation of the desired N-9 isomer from the mixture is very tedious and requires chromatographic separation or fractional crystallisation.
In addition to the above, the PCT patent specification WO 95/027281 describes a process for the synthesis of Acyclovir (Ia) from N.sup.2 -formylguanine. The chemistry of the process is illustrated in the following Scheme C: ##STR11##
As illustrated in the above scheme, acyclovir is synthesised in four steps:
The final crude product is subjected to elaborate purification steps to get guanine free acyclovir of pharmaceutical grade. It is a lengthy process and hence not practical.
It might be highlighted that in the prior art, alkylation of DAG (Va), N.sup.2 -acetyl guanine (MAG, VIa) or N.sup.2 -formylguanine to the penultimate intermediate of I is always an acid catalysed one; for instance p-toluenesulfonic acid is a common acid although other acids have also been employed [Chem Pharm Bull, 36(3), 1153-1157 (1988)]. Also use of a solvent is preferred in almost all the cases and no attempt has been made for recycle of the undesired N-7 isomer or developing conditions which can lead to selective formation of the desired isomer i.e II.
Prior art also does not specify the molar ratio of acid catalyst and alkylating agent with respect to protected guanine derivatives for obtaining high N-9/N-7 isomer ratio.